Results from the Phase III registrational EV-303/KEYNOTE-905 study evaluating the combination of Pfizer’s and Astellas’ nectin-4 targeting antibody-drug conjugate Padcev (enfortumab vedotin) and MSD’s Keytruda (pembrolizumab) for perioperative muscle-invasive bladder cancer (MIBC), were presented at the 2025 European Society of Medical Oncology (ESMO) Congress, held from October 17–21.
The combination is already the standard of care (SOC) as a first-line treatment in metastatic urothelial cancer based on the EV-302/KEYNOTE-A39 study. At the first analysis, patients, who are ineligible for cisplatin-based chemotherapy, were treated with the combination before and after surgery and had a 60% reduction in event-free survival, the trial’s primary endpoint, compared to those who received surgery alone. An estimated 74.7% of patients treated were event-free after two years compared to 39.4% who received surgery alone. Patients treated with the combination experienced a 50% reduction in risk of death, the key secondary endpoint, and an estimated 79.7% of patients treated were alive after two years compared to 63.1% who received cystectomy alone. In terms of safety, 71.3% of patients treated with the combination experienced a grade ≥3 adverse event compared to 45.9% who received surgery alone. In addition to the KEYNOTE-905, Pfizer and MSD is sponsoring a study for perioperative cisplatin-eligible patients.
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The potential of moving the combination to the earlier MIBC setting significantly increases the Padcev market. According to GlobalData’s patient-based forecast, Bladder Cancer: Eight-Market Drug Forecast and Market Analysis, Padcev sales are projected to reach $3.6bn by 2032 across the eight major markets (US, France, Germany, Italy, Spain, UK, Japan, and China).
Padcev is in line to be the first approved antibody-drug conjugate approved for perioperative bladder cancer. Specifically, for cisplatin-ineligible patients, there are no approved agents in the neoadjuvant setting, while Bristol Myers Squibb’s checkpoint inhibitor Opdivo (nivolumab) is approved in the adjuvant setting for all comers. For cisplatin-eligible patients, AstraZeneca’s Imfinzi (durvalumab) was approved in combination with chemotherapy based on the NIAGRA study. A potential threat to Padcev in the cisplatin-ineligible perioperative setting is Johnson & Johnson’s gemcitabine delivery system Inlexzo (formerly TAR 200) in combination with PD1 inhibitor cetrelimab. Interim results from the Phase II SunRISe-4 study showed the combination yielded a 38% CR rate compared to 28% with cetrelimab alone.
Assuming the Padcev and Keytruda combination is approved, and becomes the new SOC in the perioperative setting, physicians will need to contend with the possibility of those patients who progress or relapse on the treatment. For patients who progress, physicians may choose another drug class rather than retreat. For those who relapse, the question of re-exposure will likely depend on how much time has passed from the original dosing. The potential of Inlexzo entering the market could sway some physicians into choosing the gemcitabine delivery system, thereby saving Padcev for the metastatic setting.
Update: Paragraph 5 has been updated with the correct CR rate reported in the Phase II SunRISe-4 study at ESMO 2025. Paragraph 2 has been updated to describe the correct indication in which the Padcev/Keytruda combination is an SOC.
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